Itraconazole, a weak basic drug (pKa=3.7), is little soluble in water so that its bioavailability is low. Itraconazole has the low water-solubility of less than 1 ug/ml even if its solubility increases in lower pH solution (See PCT publication No. WO 01/85,135). It is well known that a rate-determining step for absorption of a poorly water-soluble drug like itraconazole largely depends on the drug's solubility and dissolution rate. Even if such a drug disintegrates completely, the drug does not dissolve in a small volume of body fluid because of its low solubility, which results in a reduced bioavailability (See pharmaceutics, hanrimwon, South Korea, p. 218).
Moreover, the solubility of some commercially available formulations containing itraconazole falls rapidly with a small increase of pH. The solubility difference between pH 1.6 and 2.4 reaches to 5.3 times (See PCT publication No. WO 01/85,135). Thus, the pH-dependence of the commercial itraconazole formulations may cause inter- and intra-individual absorption variation. For example, as for AIDS patients having a higher pH in stomach because of their poor gastric secretion, their absorption of itraconazole was reported to be no more than 50% of that of normal people (See The pharmacokinetics of oral itraconazole in AIDS patients, J. Pharm. Pharmacol., 44, 1992, p. 618). Therefore, it has been recommended to take an itraconazole formulation with a drink like a COLA that can decrease the pH of stomach. It has also been recommended to take it after meal because the higher pH of stomach before meal may reduce its absorption.
In addition, when considering that human stomach has a normal pH range of about 1 to 3.5 and the pH of stomach of almost 16% adults is over 3, a drug formulation that decreases the solubility variation in the above pH range can enlarge the absorption of itraconazole and reduce the inter- and intra-individual absorption variation (See The design and evaluation of controlled release systems for the gastro-intestinal tract, In advances in drug delivery systems, Amsterdam, 1986, p. 27-38). That is, a composition (formulation) that can increase itraconazole's solubility and prevent a decrease of solubility in the normal pH range of human stomach should be designed in order to achieve an improved bioavailability of itraconazole.
Furthermore, because the pH of human intestine is over 5, an itraconazole passing stomach without being absorbed will precipitate rapidly. This decrease of solubility may cause poor absorption and low bioavailability (See Drug delivery system, hanrimwon, Seoul, South Korea, p. 28-31). Based on this problem, the rapid dissolution of itraconazole before reaching an intestine (that is, increasing the dissolution rate of formulation) is one of important factors to improve bioavailability of an itraconazole composition.
Because of the above reasons, bioavailabilities of oral itraconazole formulations are very low and absorption variations are large depending on stomach condition of each individual including food and disease.
To solve these problems, PCT patent publication No. WO 85/02767 and U.S. Pat. No. 4,767,604 disclosed methods trying to improve the solubility and bioavailability of itraconazole by forming a complex with cyclodextrin and its derivatives. However, the method has demerits that the solubility of inclusion materials (cyclodextrin and its derivatives) decreases depending on a used solvent and it has limits such as a large manufacturing cost and the large amount and size of one preparation inevitably caused by inclusion ratio.
PCT patent publication No. WO 97/44,014 also discloses solid dispersions comprising itraconazole and a water-soluble polymer made by a melt-extrusion process in order to increase the dissolution rate and bioavailability of itraconazole. However, keeping a fixed temperature for melting drug and polymer and blocking the happening of amorphous or crystal form are difficult, which makes it difficult to control the quality of the formulation. Avoiding the change of formulation property and the happening of carbide is also difficult because of the above reasons.
PCT patent publication No. WO 94/05,236 also discloses a capsule having beads made by a process comprising: making a solution comprising itraconazole and a hydrophilic polymer, for example, hydroxypropylmethylcellulose; spray-drying the solution to coat sugar spheres of some size determined on the basis of aggregation and surface area; and re-coating the coated sugar spheres with polyethyleneglycol to make a sealing film. However, the beads may show a big difference of absorption according to stomach conditions of each individual (for example, pH and stomach retention time) and have a disadvantage that their manufacturing process is very complex. Furthermore, the process needs a large amount of organic solvent (for example, methylene chloride) to dissolve itraconazole in a spraying solution, which increases manufacturing time and make the total process cost-ineffective.
PCT patent publication No. WO 99/33,467 also discloses a method for preparing solid dispersions comprising: dissolving itraconazole and a pH-dependent hydrophilic polymer in a solvent; and spray-drying the solution to make a solid dispersion. The method can increase the solubility of itraconazole to some degree and reduce the variation caused by food intake, but it is not cost-effective because the method needs a large amount of organic solvent to dissolve itraconazole and it needs much time to spray-dry such a large amount of organic solvent. In addition, considering the pH of over 3 in stomach as described above, the solubility of the pH-dependent polymer itself may decrease in such a pH and it results in the decrease of the dissolution rate of itraconazole (See PCT publication No. WO 01/85,135).
Besides the above methods for manufacturing an itraconazole formulation with an improved solubility and rapid dissolution rate, there are many methods like vacuum-melting methods, spray-drying methods and solvent-evaporating methods. However, most methods have problems like bad yield, large manufacturing cost, long manufacturing time, complexity of process and content decrease during process.